Mammary Glands Possess Intrinsic Molecular Laterality and Respond Left- Right Differently to Genetic and Pharmacological Manipulation.

摘要

More tumors form in the left (L) breast and tumors in the right (R) breast may be more aggressive. These epidemiological findings suggest L-R differences in overall tumor biology depending on the side of tumor origin, leading to the hypothesis that mammary glands are L-R different and have discordant responses to neoplastic risk factors. Here we show that normal mammary glands are molecularly L-R different, and have more mammary stem cells (MaSCs) in the L thoracic mammary gland (TMG). In addition, MaSCs from the L and R TMGs are molecularly and functionally different in vitro and in vivo. MaSCs respond to ErbB2 and EGFR inhibition via Lapatinib treatment asymmetrically. L-side MaSCs are inhibited by Lapatinib whereas R-side MaSCs increase in self-renewal with Lapatinib treatment. MMTV-NeuTg/Tg mice overexpress the oncogene Neu also known as ErbB2 or HER2 and model HER2+ breast cancer. MMTV-Neu Tg/Tg mouse TMGs respond L-R discordantly to oncogene overexpression resulting in asymmetric ductal network formation and discordant gene regulation. Furthermore, MaSCs are increased asymmetrically enhancing L-side enrichment of MaSCs, and MaSC in vitro function was asynchronously effected. Additionally, when gene expression is inverted in the MMTV-NeuTg/Tg model, MaSC in vitro growth, self-renewal, and response to Lapatinib is also inverted. Inguinal mammary glands (IMGs) of the MMTV-Neu Tg/Tg model show delayed molecular laterality and are less sensitive to oncogene over-expression. When WT mice are exposed to estrogen (E2) neonatally, E2 induces asymmetric ductal morphogenesis, asymmetrically reduces luminal cell differentiation, and induces an asymmetric increase in MaSCs in TMGs. IMGs of E2 treated mice have no detectable L-R differences in morphology, suggesting IMGs are not as sensitive to early E2 exposure. Lastly, L-R differences in TMG development are shown to have an embryonic origin. RXRalpha +/- mice with altered embryonic development have asymmetric TMG development but not IMG development. Taken together these data show that L-R differences in TMGs originate embryonically, TMGs are lateralized organs that respond to stimulus L-R differently, and TMGs are more sensitive to perturbation than IMGs. These L-R differences in MaSC populations during normal development allow for L-R different responses to neoplasia, as well as correlate with L-R differences in patient outcome and response to therapy.