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Molecular links between breast cancer risk factors and pro-oncogenic tissue alterations are poorly understood. The goal of this study was to characterize the impact of overweight and obesity on tissue markers of risk, using normal breast biopsies, a mouse model of obesity, and cultured breast acini. Proliferation and disruption of epithelial polarity, both necessary for tumor initiation, were quantified by immunostaining. High BMI and elevated leptin were associated with compromised epithelial polarity whereas overweight was associated with proliferation in human and mice mammary glands. Human serum with unfavorable adipokine levels altered epithelial polarization of cultured acini, recapitulating the effect of leptin. Weight loss in mice led to metabolic improvements and restored epithelial polarity. In acini cultures, epithelial polarity loss was prevented by antioxidants and could be reverted by normalizing culture conditions. This study provides a framework to set target values for metabolic improvements and to assess the efficacy of interventional studies aimed at reducing breast cancer risk.