Search

Simple Summary: Breast cancer is one of the most common types of cancer in women. Breast tumors can be grouped in, at least, three different molecular subtypes, including luminal, HER2+ and triple negative subtypes. Store-operated Ca2+ entry (SOCE) is a mechanism for Ca2+ influx that supports a variety of cancer hallmarks in breast cancer cells. The key molecular players of SOCE are the endoplasmic reticulum Ca2+ sensor STIM1 and the highly Ca2+-selective Orai1 channels in the plasma membrane. The aim of the present study is to elucidate the functional role of extended synaptotagmins 1 and 2 in the activation of SOCE by facilitating the tethering of the plasma membrane and the membrane of the endoplasmic reticulum. Our results indicate that extended synaptotagmins 1 and 2 are required for SOCE, migration and viability in luminal MCF7 and triple negative breast cancer cells, without having any effect on SOCE in non-tumoral breast epithelial cells. Extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER)-associated proteins that facilitate the tethering of the ER to the plasma membrane (PM), participating in lipid transfer between the membranes and supporting the Orai1–STIM1 interaction at ER–PM junctions. Orai1 and STIM1 are the core proteins of store-operated Ca2+ entry (SOCE), a major mechanism for Ca2+ influx that regulates a variety of cellular functions. Aberrant modulation of SOCE in cells from different types of cancer has been reported to underlie the development of several tumoral features. Here we show that estrogen receptor-positive (ER+) breast cancer MCF7 and T47D cells and triple-negative breast cancer (TNBC) MDA-MB-231 cells overexpress E-Syt1 and E-Syt2 at the protein level; the latter is also overexpressed in the TNBC BT20 cell line. E-Syt1 and E-Syt2 knockdown was without effect on SOCE in non-tumoral MCF10A breast epithelial cells and ER+ T47D breast cancer cells; however, SOCE was significantly attenuated in ER+ MCF7 cells and TNBC MDA-MB-231 and BT20 cells upon transfection with siRNA E-Syt1 or E-Syt2. Consistent with this, E-Syt1 and E-Syt2 knockdown significantly reduced cell migration and viability in ER+ MCF7 cells and the TNBC cells investigated. To summarize, E-Syt1 and E-Syt2 play a relevant functional role in breast cancer cells. [ABSTRACT FROM AUTHOR]

Simple Summary: This study evaluates the occurrence of second primary neoplasms (SPNs) in individuals with a history of melanoma (MM) and identify factors that increase the risk in our population. A prospective cohort study was conducted, involving 529 MM survivors from January 2005 to August 2021. Among the 529 patients, 89 were diagnosed with SPNs, with 62 being skin tumors and 37 being solid organ tumors. The estimated probability of developing SPNs after MM diagnosis was found to increase over time, reaching 4.1% at 1 year, 11% at 5 years, and 19% at 10 years. Several factors were significantly associated with a higher risk of SPNs, including older age, primary MM location on the face or neck, and the histologic subtype of lentigo maligna MM. We conclude that individuals with primary MM located on the face and neck, as well as those with the histological subtype of lentigo maligna-MM, have a higher risk of developing SPNs. Age also independently influences the risk. Understanding these risk factors can assist in developing MM guidelines that provide specific follow-up recommendations for individuals at the highest risk. (1) Introduction: The association between melanoma (MM) and the occurrence of second primary neoplasms (SPNs) has been extensively studied, with reported incidence rates ranging from 1.5% to 20%. This study aims to evaluate the occurrence of SPNs in patients with a history of primary MM and to describe the factors that make the risk higher in our population. (2) Material and Methods: We conducted a prospective cohort study and calculated the incidence rates and relative risks (RR) for the development of different SPNs in 529 MM survivors from 1 January 2005 to 1 August 2021. Survival and mortality rates were obtained, and the Cox proportional hazards model was used to determine the demographic and MM-related factors that influence the overall risk. (3) Results: Among the 529 patients included, 89 were diagnosed with SPNs (29 prior to MM diagnosis, 11 synchronous, and 49 after MM), resulting in 62 skin tumors and 37 solid organ tumors. The estimated probability of developing SPNs after MM diagnosis was 4.1% at 1 year, 11% at 5 years, and 19% at 10 years. Older age, primary MM location on the face or neck, and histologic subtype of lentigo maligna mm were significantly associated with a higher risk of SPNs. (4) Conclusions: In our population, the risk of developing SPNs was higher in patients with primary MM located on the face and neck and with the histological subtype of lentigo maligna-MM. Age also independently influences the risk. Understanding these hazard factors can aid in the development of MM guidelines with specific follow-up recommendations for individuals with the highest risk. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer shows a high heterogeneity which accounts for cancer subtype aggressiveness. Store-operated calcium entry (SOCE) is significantly remodeled in breast cancer cells and supports a variety of cancer hallmarks. Here we show that breast cancer cells from different subtypes exhibit a variable Orai1:Orai2 expression ratio. In cells with a high Orai2 expression, Orai2 modulates the magnitude SOCE and support Ca2+ oscillations in response to agonists, thus modulating the activation of the transcription factors NFAT1 and NFAT4. Furthermore, Orai2 plays a relevant role in cell cycle progression and apoptosis resistance. Breast cancer is a heterogeneous disease from the histological and molecular expression point of view, and this heterogeneity determines cancer aggressiveness. Store-operated Ca2+ entry (SOCE), a major mechanism for Ca2+ entry in non-excitable cells, is significantly remodeled in cancer cells and plays an important role in the development and support of different cancer hallmarks. The store-operated CRAC (Ca2+ release-activated Ca2+) channels are predominantly comprised of Orai1 but the participation of Orai2 and Orai3 subunits has been reported to modulate the magnitude of Ca2+ responses. Here we provide evidence for a heterogeneous expression of Orai2 among different breast cancer cell lines. In the HER2 and triple negative breast cancer cell lines SKBR3 and BT20, respectively, where the expression of Orai2 was greater, Orai2 modulates the magnitude of SOCE and sustain Ca2+ oscillations in response to carbachol. Interestingly, in these cells Orai2 modulates the activation of NFAT1 and NFAT4 in response to high and low agonist concentrations. Finally, we have found that, in cells with high Orai2 expression, Orai2 knockdown leads to cell cycle arrest at the G0-G1 phase and decreases apoptosis resistance upon cisplatin treatment. Altogether, these findings indicate that, in breast cancer cells with a high Orai2 expression, Orai2 plays a relevant functional role in agonist-evoked Ca2+ signals, cell proliferation and apoptosis resistance. [ABSTRACT FROM AUTHOR]

Breast cancer is a heterogeneous disease from the histological and molecular expression point of view, and this heterogeneity determines cancer aggressiveness. Store-operated Ca 2+ entry (SOCE), a major mechanism for Ca 2+ entry in non-excitable cells, is significantly remodeled in cancer cells and plays an important role in the development and support of different cancer hallmarks. The store-operated CRAC (Ca 2+ release-activated Ca 2+ ) channels are predominantly comprised of Orai1 but the participation of Orai2 and Orai3 subunits has been reported to modulate the magnitude of Ca 2+ responses. Here we provide evidence for a heterogeneous expression of Orai2 among different breast cancer cell lines. In the HER2 and triple negative breast cancer cell lines SKBR3 and BT20, respectively, where the expression of Orai2 was greater, Orai2 modulates the magnitude of SOCE and sustain Ca 2+ oscillations in response to carbachol. Interestingly, in these cells Orai2 modulates the activation of NFAT1 and NFAT4 in response to high and low agonist concentrations. Finally, we have found that, in cells with high Orai2 expression, Orai2 knockdown leads to cell cycle arrest at the G0-G1 phase and decreases apoptosis resistance upon cisplatin treatment. Altogether, these findings indicate that, in breast cancer cells with a high Orai2 expression, Orai2 plays a relevant functional role in agonist-evoked Ca 2+ signals, cell proliferation and apoptosis resistance.